tbuckley/cabot-search huggingface dataset:
Neural Signatures of Pain Modulation in Short-Term and Long-Term Mindfulness Training: A Randomized Active-Control Trial
Authors: Joseph Wielgosz, Tammi R.A. Kral, David M. Perlman, Jeanette A. Mumford, Tor D. Wager, Antoine Lutz, Richard J. Davidson
Journal: American Journal of Psychiatry (2022)

Mindfulness-based interventions are widely used to target pain, yet their neural mechanisms of action are insufficiently understood. The authors studied neural and subjective pain response in a randomized active-control trial of mindfulness-based stress reduction (MBSR) alongside long-term meditation practitioners.Healthy participants (N=115) underwent functional neuroimaging during a thermal acute pain task before and after random assignment to MBSR (N=28), an active control condition (health enhancement program [HEP]) (N=32), or a waiting list control condition (N=31). Long-term meditators (N=30) completed the same neuroimaging paradigm. Pain response was measured via self-reported intensity and unpleasantness, and neurally via two multivoxel machine-learning-derived signatures: the neurologic pain signature (NPS), emphasizing nociceptive pain processing, and the stimulus intensity independent pain signature-1 (SIIPS1), emphasizing stimulus-independent neuromodulatory processes.The MBSR group showed a significant decrease in NPS response relative to the HEP group (Cohen's d=-0.43) and from pre- to postintervention assessment (d=-0.47). The MBSR group showed small, marginal decreases in NPS relative to the waiting list group (d=-0.36), and in SIIPS1 relative to both groups (HEP group, d=-0.37; waiting list group, d=-0.37). In subjective unpleasantness, the MBSR and HEP groups also showed modest significant reductions compared with the waiting list group (d=-0.45 and d=-0.55). Long-term meditators reported significantly lower pain than nonmeditators but did not differ in neural response. Within the long-term meditator group, cumulative practice during intensive retreat was significantly associated with reduced SIIPS1 (r=-0.65), whereas daily practice was not.Mindfulness training showed associations with pain reduction that implicate differing neural pathways depending on extent and context of practice. Use of neural pain signatures in randomized trials offers promise for guiding the application of mindfulness interventions to pain treatment.
Impact of COVID-19 Telehealth Policy Changes on Buprenorphine Treatment for Opioid Use Disorder
Authors: Lewei (Allison) Lin, Lan Zhang, Hyungjin Myra Kim, Madeline C. Frost
Journal: American Journal of Psychiatry (2022)

The authors examined the impact of COVID-19-related policies reducing barriers to telehealth delivery of buprenorphine treatment for opioid use disorder (OUD) on buprenorphine treatment across different modalities (telephone, video, and in-person visits).
ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia
Authors: Lioba Schönfeld, Jenny Rinke, Anna Hinze, Saskia N. Nagel, Vivien Schäfer, Thomas Schenk, Christian Fabisch, Tim H. Brümmendorf, Andreas Burchert, Philipp le Coutre, Stefan W. Krause, Susanne Saussele, Fatemeh Safizadeh, Markus Pfirrmann, Andreas Hochhaus, Thomas Ernst
Journal: Leukemia (2022)

Abstract Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected ( n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.
Trends in Cannabis Use Disorder Diagnoses in the U.S. Veterans Health Administration, 2005–2019
Authors: Deborah S. Hasin, Andrew J. Saxon, Carol Malte, Mark Olfson, Katherine M. Keyes, Jaimie L. Gradus, Magdalena Cerdá, Charles C. Maynard, Salomeh Keyhani, Silvia S. Martins, David S. Fink, Ofir Livne, Zachary Mannes, Melanie M. Wall
Journal: American Journal of Psychiatry (2022)

In the United States, adult cannabis use has increased over time, but less information is available on time trends in cannabis use disorder. The authors used Veterans Health Administration (VHA) data to examine change over time in cannabis use disorder diagnoses among veterans, an important population subgroup, and whether such trends differ by age group (&lt;35 years, 35-64 years, ≥65 years), sex, or race/ethnicity.
The epitranscriptome in ageing and stress resistance: A systematic review
Authors: Anja Wagner, Markus Schosserer
Journal: Ageing Research Reviews (2022)

Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just beginning to be studied in the context of ageing and stress resistance. RNA modifications modulate gene expression by affecting translation initiation and speed, miRNA binding, RNA stability, and RNA degradation. Nonetheless, the precise underlying molecular mechanisms and physiological consequences of most alterations of the epitranscriptome are still only poorly understood. We here systematically review different types of modifications of rRNA, tRNA and mRNA, the methodology to analyze them, current challenges in the field, and human disease associations. Furthermore, we compiled evidence for a connection between individual enzymes, which install RNA modifications, and lifespan in yeast, worm and fly. We also included resistance to different stressors and competitive fitness as search criteria for genes potentially relevant to ageing. Promising candidates identified by this approach include RCM1/NSUN5, RRP8, and F33A8.4/ZCCHC4 that introduce base methylations in rRNA, the methyltransferases DNMT2 and TRM9/ALKBH8, as well as factors involved in the thiolation or A to I editing in tRNA, and finally the m6A machinery for mRNA.
Abstract Supplement ACR Convergence 2020
Authors: Chloé Comarmond, Mathilde Leclercq, Gaëlle Leroux, Cindy Marques, Alexandre Le Joncour, Fanny Domont, Céline Hatte, Ségolène Toquet, Perrine Guillaume-Jugnot, Anne-Claire Desbois, Mathieu Vautier, Aude Rigolet, Yves Allenbach, Olivier Benveniste, David Saadoun, Patrice Cacoub
Journal: Arthritis & Rheumatology (2020)

Abstract For a searchable version of these abstracts, please visit www.acrabstracts.org .
Tonsillar transcriptional profiles in atopic and non‐atopic subjects
Authors: Tanzeela Hanif, Lotta E. Ivaska, Freed Ahmad, Ge Tan, Emilia Mikola, Tuomo Puhakka, Oscar Palomares, Cezmi A. Akdis, Sanna Toppila‐Salmi, Tuomas Jartti
Journal: Allergy (2022)

Emerging research suggests that local lymphatic tissue such as tonsils have important role in regulating the immune responses. However, allergen sensitization-induced alterations in transcriptome of tonsils are not known.To examine the key differences in tonsillar gene expression between atopic and non-atopic subjects and further by type of sensitization.RNA-sequencing was performed on 52 tonsillar samples from atopic and non-atopic tonsillectomy patients. Sensitization to common food- and aero-allergen was defined by allergen specific IgE. Following groups were studied: (1) aero- and food-allergen sensitized (AS+FS) versus non-sensitized (NS), (2) aeroallergen-sensitized (AS) versus food-allergen sensitized (FS), (3) AS versus NS, (4) FS versus NS. Bioinformatics analysis was done using DESeq2(v3.10.2), WGCNA and GATK pipeline in R software (v3.3.1). Protein-protein interaction network was made from String database.We studied 13 aeroallergen-sensitized, 6 food-allergen sensitized, 4 both food-and aero-allergen-sensitized and 29 non-sensitized tonsillectomy patients. Overall, 697 unique differentially expressed genes (DEGs) were detected in all sensitized subgroups including chemokines (CXCL2, CXCL8, CXCL10, CXCL11), IL-20RA, MUC1 and MUC20. When comparing different groups, the gene expression profiles overlapped except the AS versus FS group comparison, suggesting significantly different gene expression between the two sensitization subgroups. Furthermore, aeroallergen-sensitized subjects had more prominent immune responses compared with non-sensitized and food-allergen sensitized subjects including gene expression for IL-17 pathway and Toll-like receptor signalling pathway.Allergic sensitization is associated with extensive tonsillar transcriptomic alterations and changes in immune related genes and pathways. Distinct differences were found between aero-allergen and food-allergen sensitization.
Dupilumab reduced impact of severe exacerbations on lung function in patients with moderate‐to‐severe type 2 asthma
Authors: Alberto Papi, Jonathan Corren, Mario Castro, Christian Domingo, Linda Rogers, Kenneth R. Chapman, Daniel J. Jackson, Nadia Daizadeh, Nami Pandit‐Abid, Rebecca Gall, Juby A. Jacob‐Nara, Paul J. Rowe, Yamo Deniz, Benjamin Ortiz
Journal: Allergy (2022)

Severe asthma exacerbations increase the risk of accelerated lung function decline. This analysis examined the effect of dupilumab on forced expiratory volume in 1 s (FEV1 ) in patients with moderate-to-severe asthma and elevated type 2 biomarkers from phase 3 LIBERTY ASTHMA QUEST (NCT02414854).Changes from baseline in pre- and post-bronchodilator (BD) FEV1 and 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients with elevated type 2 biomarkers at baseline (type 2-150/25: eosinophils ≥150 cells/μl and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb; type 2-300/25: eosinophils ≥300 cells/μl and/or FeNO ≥25 ppb), stratified as exacerbators (≥1 severe exacerbation during the study) or non-exacerbators.In exacerbators and non-exacerbators, dupilumab increased pre-BD FEV1 by Week 2 vs placebo; differences were maintained to Week 52 (type 2-150/25: LS mean difference (LSMD) vs placebo: 0.17 L (95% CI: 0.10-0.24) and 0.17 L (0.12-0.23); type 2-300/25: 0.22 L (0.13-0.30) and 0.21 L (0.15-0.28)), in exacerbators and non-exacerbators, respectively (p < .0001). Similar trends were seen for post-BD FEV1 . Dupilumab vs placebo also showed significantly greater improvements in post-BD FEV1 0-42 days after first severe exacerbation in type 2-150/25 (LSMD vs placebo: 0.13 L [0.06-0.20]; p = .006) and type 2-300/25 (0.14 L [0.06-0.22]; p = .001) patients. ACQ-5 improvements were greater with dupilumab vs placebo in both groups.Dupilumab treatment led to improvements in lung function independent of exacerbations and appeared to reduce the impact of exacerbations on lung function in patients who experienced a severe exacerbation during the study.
Detergent exposure induces epithelial barrier dysfunction and eosinophilic inflammation in the esophagus
Authors: Alfred D. Doyle, Mia Y. Masuda, Grace C. Pyon, Huijun Luo, Arina Putikova, William E. LeSuer, Samuel Flashner, Matthew A. Rank, Hiroshi Nakagawa, Hirohito Kita, Benjamin L. Wright
Journal: Allergy (2022)

Abstract Background Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with type 2 inflammation and epithelial barrier dysfunction. The etiology is unknown, however, genetic heritability studies suggest environmental factors play a key role in pathogenesis. Detergents, such as sodium dodecyl sulfate (SDS), are common ingredients in household products such as dish soap and toothpaste. We hypothesized detergent exposure decreases epithelial barrier function and induces esophageal inflammation. Methods Immortalized esophageal epithelial cells (EPC2) were cultured in air‐liquid interface (ALI) and exposed to SDS. Barrier function/activity was assessed by transepithelial electrical resistance (TEER), FITC‐dextran flux, and RT‐PCR. Additionally, SDS‐treated mouse esophageal organoids were evaluated for morphology. To investigate the effects of SDS in vivo, mice were treated with 0.5% SDS in drinking water for 14 days. Esophagi were assessed by gross morphology, histopathology, protein expression, and bulk RNA sequencing. Results When EPC2 cells were exposed to SDS (5 μg/ml) for 96 h, TEER decreased ( p = 0.03), and FITC‐dextran flux increased ( p = 0.0002). mRNA expression of IL‐33 increased 4.5‐fold ( p = 0.02) at 6 h and DSG1 decreased ( p &lt; 0.0001) by 72 h. Disrupted epithelial integrity was noted in SDS‐treated esophageal organoids. When mice were exposed to SDS, they showed increased esophageal width, chemokine, and metalloprotease levels. Mice treated with SDS also showed increased IL‐33 protein expression, basal zone hyperplasia, CD4 + cell infiltration, and esophageal eosinophilia. RNA sequencing revealed upregulation of immune response pathway genes. Conclusion Exposure to SDS decreases esophageal barrier integrity, stimulates IL‐33 production, and promotes epithelial hyperplasia and tissue eosinophilia. Detergents may be a key environmental trigger in EoE pathogenesis.
Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation
Authors: Qing Wan, Chuansheng Xu, Liyuan Zhu, Yuze Zhang, Zekun Peng, Hong Chen, Haojie Rao, Erli Zhang, Hongyue Wang, Fei Chu, Xuan Ning, Xuejian Yang, Jinqing Yuan, Yongjian Wu, Yu Huang, Shengshou Hu, De-Pei Liu, Miao Wang
Journal: Circulation Research (2022)

Background: Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. Methods: Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. Results: Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow–derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide–dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. Conclusions: PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.
Extracellular Vesicle Mimetics: Preparation from Top‐Down Approaches and Biological Functions
Authors: Yuan Du, Hongyi Wang, Yang Yang, Jianfeng Zhang, Yue Huang, Shunwu Fan, Chenhui Gu, Liqing Shangguan, Xianfeng Lin
Journal: Advanced Healthcare Materials (2022)

Extracellular vesicles (EVs) have attracted attention as delivery vehicles due to their structure, composition, and unique properties in regeneration and immunomodulation. However, difficulties during production and isolation processes of EVs limit their large-scale clinical applications. EV mimetics (EVMs), prepared via top-down strategies that improve the yield of nanoparticles while retaining biological properties similar to those of EVs have been used to address these limitations. Herein, the preparation of EVMs is reviewed and their characteristics in terms of structure, composition, targeting ability, cellular uptake mechanism, and immunogenicity, as well as their strengths, limitations, and future clinical application prospects as EV alternatives are summarized.
Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis
Authors: Jiang-Yun Luo, Chak Kwong Cheng, Lei He, Yujie Pu, Yang Zhang, Xiao Lin, Aimin Xu, Chi Wai Lau, Xiao Yu Tian, Ronald Ching Wan Ma, Hanjoong Jo, Yu Huang
Journal: Circulation Research (2022)

Background: Inflamed endothelial cells (ECs) trigger atherogenesis, especially at arterial regions experiencing disturbed blood flow. UCP2 (Uncoupling protein 2), a key mitochondrial antioxidant protein, improves endothelium-dependent relaxation in obese mice. However, whether UCP2 can be regulated by shear flow is unknown, and the role of endothelial UCP2 in regulating inflammation and atherosclerosis remains unclear. This study aims to investigate the mechanoregulation of UCP2 expression in ECs and the effect of UCP2 on endothelial inflammation and atherogenesis. Methods: In vitro shear stress simulation system was used to investigate the regulation of UCP2 expression by shear flow. EC-specific Ucp2 knockout mice were used to investigate the role of UCP2 in flow-associated atherosclerosis. Results: Shear stress experiments showed that KLF2 (Krüppel-like factor 2) mediates fluid shear stress-dependent regulation of UCP2 expression in human aortic and human umbilical vein ECs. Unidirectional shear stress, statins, and resveratrol upregulate whereas oscillatory shear stress and proinflammatory stimuli inhibit UCP2 expression through altered KLF2 expression. KLF2 directly binds to UCP2 promoter to upregulate its transcription in human umbilical vein ECs. UCP2 knockdown induced expression of genes involved in proinflammatory and profibrotic signaling, resulting in a proatherogenic endothelial phenotype. EC-specific Ucp2 deletion promotes atherogenesis and collagen production. Additionally, we found endothelial Ucp2 deficiency aggravates whereas adeno-associated virus-mediated EC- Ucp2 overexpression inhibits carotid atherosclerotic plaque formation in disturbed flow-enhanced atherosclerosis mouse model. RNA-sequencing analysis revealed FoxO1 (forkhead box protein O1) as the major proinflammatory transcriptional regulator activated by UCP2 knockdown, and FoxO1 inhibition reduced vascular inflammation and disturbed flow-enhanced atherosclerosis. We showed further that UCP2 level is critical for phosphorylation of AMPK (AMP-activated protein kinase), which is required for UCP2-induced inhibition of FoxO1. Conclusions: Altogether, our studies uncover that UCP2 is novel mechanosensitive gene under the control of fluid shear stress and KLF2 in ECs. UCP2 expression is critical for endothelial proinflammatory response and atherogenesis. Therapeutic strategies enhancing UCP2 level may have therapeutic potential against atherosclerosis.
NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis
Authors: Xiaoman Bi, Qing Zhang, Lei Chen, Dan Liu, Yueying Li, Xiaoxi Zhao, Ya Zhang, Liping Zhang, Jingkun Liu, Chaoyi Wu, Zhigang Li, Yunze Zhao, Honghao Ma, Gang Huang, Xin Liu, Qian-fei Wang, Rui Zhang
Journal: Journal of Hematology & Oncology (2022)

Abstract Hemophagocytic lymphohistiocytosis (HLH), particularly primary HLH (pHLH), is a rare, life-threatening disease. Germline genetic deficiency of 12 known HLH genes impairs cytotoxic degranulation in natural killer (NK) cells or cytotoxic T lymphocytes (CTLs) and contributes to pHLH development. However, no pathogenic mutations in these HLH genes are found in nearly 10% of HLH patients, despite a strong suspicion of pHLH, suggesting that the underlying genetic basis of HLH is still unclear. To discover novel susceptibility genes, we first selected 13 children with ppHLH (presumed primary HLH patients in the absence of detectable known HLH gene variants) and their parents for initial screening. Whole-genome sequencing (WGS) in one trio and whole-exome sequencing (WES) in twelve trios revealed that two ppHLH patients carried biallelic NBAS variants, a gene that is involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport upstream of the degranulation pathway. Additionally, two candidate genes, RAB9B and KLC3 , showed a direct relationship with known HLH genes in protein-protein interaction (PPI) network analysis. We analyzed NBAS , RAB9B , KLC3 and known HLH genes in an independent validation cohort of 224 pediatric HLH patients. Only biallelic NBAS variants were identified in three patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS -deficient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus. According to our findings, NBAS is the second most frequently mutated gene (2.11%) in our HLH cohort after PRF1 . NBAS deficiency may contribute to the development of HLH via a dysregulated lytic vesicle transport pathway.
Abstract Book: 25th Congress of the European Hematology Association Virtual Edition, 2020
Journal: HemaSphere (2020)

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